Over the past few decades, research on the peptide hormone, relaxin, has significantly improved our understanding of its biological actions under physiological and diseased conditions. This has facilitated the conducting of clinical trials to explore the use of serelaxin (human recombinant relaxin). Acute heart failure (AHF) is a very difficult to treat clinical entity, with limited success so far in developing new drugs to combat it. A recent phase-III RELAX-AHF trial using serelaxin therapy given during hospitalization revealed acute (ameliorated dyspnea) and chronic (improved 180-day survival) effects. Although these findings support a substantial improvement by serelaxin therapy over currently available therapies for AHF, they also raise key questions and stimulate new hypotheses. To facilitate the development of serelaxin as a new drug for heart disease, joint efforts of clinicians, research scientists and pharmacological industries are necessary to study these questions and hypotheses. In this review, after providing a brief summary of clinical findings and the pathophysiology of AHF, we present a working hypothesis of the mechanisms responsible for the observed efficacy of serelaxin in AHF patients. The existing clinical and preclinical data supporting our hypotheses are summarized and discussed. The development of serelaxin as a drug provides an excellent example of the bilateral nature of translational research.  (Circ J 2014; 78: 542–552)

View full abstract

Peripheral artery disease (PAD) usually refers to ischemia of the lower limb vessels. Currently, the estimated number of cases in the world is 202 million. PAD is the third leading cause of atherosclerotic cardiovascular morbidity. The measurement of the ankle-brachial index (ABI) is recommended as a first-line noninvasive test for screening and diagnosis of PAD. An ABI <0.90 is an independent predictor of cardiovascular events and this measurement is useful to identify patients at moderate to high risk of cardiovascular disease. However, there is insufficient evidence to assess the benefits and harms of screening for PAD with the ABI in asymptomatic adults. Lifestyle modifications, including smoking cessation, dietary changes and physical activity, are currently the most cost-effective interventions. Inverse associations with PAD have been reported for some subtypes of dietary fats, fiber, antioxidants (vitamins E and C), folate, vitamins B6, B12 and D, flavonoids, and fruits and vegetables. A possible inverse association between better adherence to the Mediterranean diet and the risk of symptomatic PAD has also been reported in a large randomized clinical trial. Therefore, a Mediterranean-style diet could be effective in the primary and secondary prevention of PAD, although further experimental studies are needed to better clarify this association.  (Circ J 2014; 78: 553–559)

View full abstract

Mitral valve repair is the gold standard treatment for mitral regurgitation. The history of mitral valve repair and its refinement in terms of the technique used will show the evolution of this surgical technique. The standard technique we use for mitral valve repair is described, and the outcomes we have observed over the past 4 decades are presented.  (Circ J 2014; 78: 560–566)

View full abstract

Despite the recent progress in the diagnosis and treatment of cardiovascular diseases, these are still a major source of morbidity and mortality worldwide. For this reason, a large research effort was directed to the identification of the underlying pathophysiological aspects of cardiovascular diseases. Nevertheless, many mechanisms still need to be more deeply investigated, limiting the development of efficient diagnostic and therapeutic strategies for a relevant number of patients. Recently, microRNAs (miRs) emerged as powerful regulators of biological processes, offering a further opportunity to better understand the biological mechanisms responsible for the development of cardiovascular diseases, including cellular function and cell-to-cell communication. At the same time, the recent demonstration that cell-derived circulating miRs can be measured in the blood opens up their use as powerful biomarkers. The present review summarizes the most relevant experimental evidences on the involvement of miRs in cardiovascular diseases, including vascular remodeling, coronary artery disease, heart failure and ischemic stroke, thus highlighting potential targets for novel therapeutic strategies.  (Circ J 2014; 78: 567–575)

View full abstract

As the link between heart failure (HF) and diabetes mellitus (DM) becomes unignorable, so the need is further increasing for pathological comprehension: What is “diabetic cardiomyopathy (DMC)?” In response to current concern, the most updated guidelines stated by the ACCF/AHA and by the ESC/EASD take one step further, including the definition of DMC, although it is a matter yet to be completed. For more than 40 years, coronary artery disease and hypertension have been considered as the main causes of diabetes-related cardiac dysfunction. HF was originally considered as a result of reduced left ventricular ejection fraction (HF-REF); however, it has been recognized that HF symptoms are often observed in patients with preserved EF (HF-PEF). DMC includes HF with both reduced and preserved entities independent of coronary stenosis and hypertension. Cardiologists are thus facing a sort of chaos without clear guidelines for the “deadly intersection” of DM and HF. Today, the increasing interest and concern have caused DMC to be revisited and the first step in controlling the chaos around DMC is to organize and analyze all of the available evidence from preclinical and clinical studies. This review aims to illustrate the current concepts of DMC by shedding light on the new molecular mechanisms.  (Circ J 2014; 78: 576–583)

View full abstract

Background: The relationship between pulmonary vein (PV) potential (PVP) disappearance patterns during encircling ipsilateral pulmonary vein isolation (EIPVI) of atrial fibrillation (AF), and outcome was examined. Methods and Results: A total of 352 consecutive AF patients (age, 61±12 years; 269 men, 76.4%; paroxysmal AF, n=239; persistent AF, n=73; and long-standing persistent AF, n=40) who underwent initial AF ablation were studied. After EIPVI with a double Lasso technique, pacing was performed from the PV carina to confirm isolation of the carina. PVP disappearance patterns were classified into 3 types: A, both superior and inferior PVP disappeared simultaneously; B, superior and inferior PVP disappeared separately; and C, additional RF applications were required inside the encircling lesions to eliminate the PVP after creating anatomical encircling lesions. The relationship between these patterns and outcome was examined. Six groups were defined according to the combination of right and left ipsilateral PVP disappearance patterns. The incidence of A-A, A-B, B-B, A-C, B-C, and C-C was 7.1%, 14.2%, 16.2%, 15.3%, 27.3%, and 19.9%, respectively. AF recurrence-free rate at 2 years for these 6 groups was 96%, 81%, 78%, 64%, 64%, and 59%, respectively (P<0.02). The incidence of a carina isolation was 153/154 (99.4%) for type A, 221/259 (85.3%) for type B, and 145/290 (50.0%) for type C. Conclusions: PVP disappearance pattern during EIPVI was significantly associated with the incidence of residual PV carina conduction and AF recurrence.  (Circ J 2014; 78: 601–609)

View full abstract

Background: KCNE1 encodes a modulator of KCNH2 and KCNQ1 delayed rectifier K⁺ current channels. KCNE1 mutations might cause long QT syndrome (LQTS) by impairing KCNE1 subunit’s modulatory actions on these channels. There are major and minor polymorphismic KCNE1 variants whose 38^th amino acids are glycine and serine [KCNE1(38G) and KCNE1(38S) subunits], respectively. Despite its frequent occurrence, the influence of this polymorphism on the K⁺ channels’ function is unclear. Methods and Results: Patch-clamp recordings were obtained from human embryonic kidney -293T cells. KCNH2 channel current density in KCNE1(38S)-transfected cells was smaller than that in KCNE1(38G)-transfected cells by 34%. The voltage-sensitivity of the KCNQ1 channel current in KCNE1(38S)-transfected cells was lowered compared to that in KCNE1(38G)-transfected cells, with a +13mV shift in the half-maximal activation voltage. KCNH2 channel current density or KCNQ1 channel voltage-sensitivity was not different between KCNE1(38G)-transfected cells and cells transfected with both KCNE1(38G) and KCNE1(38S). Moreover, the KCNH2 channel current in KCNE1(38S)-transfected cells was more susceptible to E4031, a QT prolonging drug and a condition with hypokalemia, than that in KCNE1(38G)-transfected cells. Conclusions: Homozygous inheritance of KCNE1(38S) might cause a mild reduction of the delayed rectifier K⁺ currents and might thereby increase an arrhythmogenic potential particularly in the presence of QT prolonging factors. By contrast, heterozygous inheritance of KCNE1(38G) and KCNE1(38S) might not affect the K⁺ currents significantly.  (Circ J 2014; 78: 610–618)

View full abstract

Background: Transcatheter left atrial appendage (LAA) closure is an alternative therapy for stroke prevention in atrial fibrillation (AF) patients. However; real-world efficacy, safety and complications have yet to be investigated. We sought to determine the procedural outcomes and potential complications of LAA closure in routine clinical practice at a high-volume center. Methods and Results: The study group comprised 179 patients (105 males; 72.7±9.0 years) with AF undergoing LAA closure at a single center in Germany. The rate of successful implantation was 98.9% (2 patients did not undergo implantation) and the overall procedure-related complication rate was 11.2% (major: 3.3%: tamponade 2; possibility of transient ischemic attack (TIA) 1; device dislocation 3; minor: 7.8%: pericardial effusion 2; air embolization with transient ST segment elevation 3; thrombus on device/sheath 3; puncture complications 5). At 45 days; 99.4% showed successful sealing of the LAA and 94.5% discontinued oral anticoagulation (OAC). TIA occurred in 2 patients during 6-month follow-up; but no cases of stroke were reported. There were no hemorrhagic stroke or device-related deaths. Only 1 patient was hospitalized with traumatic subdural hematoma. Minor bleeding was reported in 5 patients. Conclusions: Transcatheter LAA closure in a high-volume center is safe and feasible. Life-threatening complications are rare. Discontinuation of OAC 45 days after implantation was also safe.  (Circ J 2014; 78: 619–624)

View full abstract

Background: The continuous flow (CF) left ventricular assist device (LVAD) has replaced the pulsatile flow (PF) LVAD because of its advantages of better patient survival and higher quality of life. However, “late-onset right ventricular failure (RVF)” after CF LVAD implantation has emerged as an increasing concern, but little is known about the mechanism. Methods and Results: We retrospectively analyzed the 3-month hemodynamic and echocardiographic data from 38 consecutive patients who had received CF LVADs, and from 22 patients who had received PF LVADs. Late-onset RVF was defined as persistent right ventricular stroke work index (RVSWI) <4.0g/m² at any rotation speed and after saline infusion test at 5 weeks after implantation of CF LVAD. Patients with late-onset RVF had significantly impaired exercise tolerance indicated by shorter 6-min walking distance and lower peak VO₂, and worsened tricuspid regurgitation, together with enlargement of the RV under CF LVAD treatment (all P<0.05). Univariable analyses demonstrated that preoperative smaller LV diastolic diameter (LVDd) was the risk factor for late-onset RVF with a cutoff value of 64mm calculated by ROC analysis (area under curve, 0.925). In contrast, there was no correlation between preoperative LVDd and postoperative RVSWI in the PF LVAD group, though their preoperative background was worse than that of the CF group. Conclusions: In the setting of preoperative small LVDd, CF LVAD may cause late-onset RVF by leftward shift of the interventricular septum.  (Circ J 2014; 78: 625–633)

View full abstract

Background: Although emergency care of acute myocardial infarction (AMI) could theoretically be improved through improved patient delay, this notion remains to be confirmed. Additionally, the influence of large earthquakes on the emergency care of AMI cases remains to be elucidated. The Great East Japan Earthquake (March 11, 2011) has enabled us to address these issues. Methods and Results: We analyzed the data from 2008 to 2011 (n=3,937) in the Miyagi AMI Registry Study. In-hospital mortality was significantly lower in 2011 as compared with the previous 3 years (7.3% vs. 10.5%, P<0.05). This improvement was noted especially during the first 2 months after the Earthquake, associated with shorter elapsing time from onset to admission (120 vs. 240min, P<0.001) and higher performance rate of primary percutaneous coronary intervention (PCI) (86.8% vs. 76.2%, P<0.01). Importantly, after the Earthquake, patients with early admission (≤3h from onset) was significantly increased (59.1% vs. 47.0%, P<0.05) and their prognosis became better (7.9% vs. 11.4%, P=0.02), associated with a lower prevalence of heart failure on admission (6.9% vs. 16.2%, P=0.02) and higher performance rate of primary PCI (89.1% vs. 76.4%, P<0.01). Conclusions: Emergency care of AMI improved soon after the Great East Japan Earthquake compared with ordinary times by the contribution of earlier admission from onset and higher performance rate of primary PCI.  (Circ J 2014; 78: 634–643)

View full abstract

Background: Few studies have assessed the effect of multiple health conditions among patients with heart disease, particularly the economic implications of having multiple conditions. Methods and Results: This study used a microsimulation model, Health&WealthMOD, to assess the effect of comorbidities on the labor force participation of 45–64-year-old Australians with heart disease, and the indirect economic costs to these individuals and government. For most comorbid conditions, there is a significant increase in the chance of an individual being out of the labor force, relative to those with heart disease alone. For example, individuals with heart disease and arthritis have more than 6-fold the odds of being out of the labor force relative to those with heart disease alone (OR 6.64, 95% CI: 2.46–17.95). People with heart disease and ≥1 comorbidities also receive a significantly lower income, pay less in taxation and receive more in government transfer payments than those with heart disease alone. Conclusions: It is important to consider whether an individual with heart disease also has other health conditions, as individuals with comorbidities have inferior financial situations and are a greater burden on government finances than those with only heart disease.  (Circ J 2014; 78: 644–648)

View full abstract

Background: Weight gain is an important risk factor of coronary artery disease, but there is limited evidence for an effect of weight change on heart failure (HF) mortality. Methods and Results: A total of 61,571 subjects aged 40–79 years were selected. Participants were already enrolled in the Japan Collaborative Cohort (JACC) study, for whom data regarding weight at the age of 20 years of age were available. The underlying causes of death were determined based on the International Classification of Diseases. During the median 19.3-year follow-up of the cohort, there were 640 deaths from myocardial infarction (MI) and 605 deaths from HF. Men and women who had gained weight had a higher risk of mortality from MI, whereas those who had lost weight had a higher risk of mortality from HF. Compared to subjects with no weight change (within ±5.0kg), the multivariate hazard ratios (HR; 95% confidence interval [CI]) of MI for weight change of +10.0kg or more were 1.51 (1.11–2.06) for men and 1.80 (1.23–2.64) for women, whereas HRs of HF were 0.76 (0.51–1.13) and 0.94 (0.66–1.33), respectively. The corresponding HRs of MI for weight change of −10.0kg or more were 0.86 (0.57–1.31) for men and 0.90 (0.54–1.53) for women, whereas those of HF were 1.33 (0.93–1.89) and 1.48 (1.04–2.12), respectively. Conclusions: High BMI and weight gain are associated with increased risk of mortality from MI, whereas low BMI and weight loss are associated with increased risk of mortality from HF.  (Circ J 2014; 78: 649–655)

View full abstract

Background: Microalbuminuria is known as a risk factor for hypertension. Recently it was suggested that urine albumin-to-creatinine ratio (UACR), even within the normal range, can be associated with hypertension, but the temporal relationship between normal range UACR and hypertension was not confirmed. Therefore the aim of this study was to verify an association between normal range UACR and the development of hypertension in Korean men. Methods and Results: This prospective cohort study was performed on 1,284 initially non-hypertensive Korean men. The total follow-up period was 4,109.5 person-years and the mean follow-up period was 3.2±1.51 years. Cox proportional hazards model was used to estimate the hazard ratios (HR) for the risk of hypertension development. After adjusting for multiple covariates, the HR (95% confidence interval [CI]) for incident hypertension, comparing the second to the fourth quartiles of UACR level to the first quartile, were 1.35 (95% CI: 0.93–1.97), 1.55 (95% CI: 1.07–2.25) and 1.89 (95% CI: 1.31–2.71), respectively (P for trend=0.001). Conclusions: High UACR within the normal range was significantly associated with hypertension development. Furthermore, this association remained significant after adjusting for multiple baseline covariates.  (Circ J 2014; 78: 656–661)

View full abstract

Background: The purpose of this study was to evaluate a personalized protocol with diluted contrast material (CM) for coronary computed tomography angiography (CTA). Methods and Results: One hundred patients with suspected coronary artery disease underwent retrospective electrocardiogram-gated coronary CTA on a 256-slice multidetector-row CT scanner. In the diluted CM protocol (n=50), the optimal scan timing and CM dilution rate were determined by the timing bolus scan, with 20% CM dilution (5ml/s during 10s) being considered suitable to achieve the target arterial attenuation of 350 Hounsfield units (HU). In the body weight (BW)-adjusted protocol (n=50, 222mg iodine/kg), only the optimal scan timing was determined by the timing bolus scan. The injection rate and volume in the timing bolus scan and real scan were identical between the 2 protocols. We compared the means and variations in coronary attenuation between the 2 protocols. Coronary attenuation (mean±SD) in the diluted CM and BW-adjusted protocols was 346.1±23.9 HU and 298.8±45.2 HU, respectively. The diluted CM protocol provided significantly higher coronary attenuation and lower variance than did the BW-adjusted protocol (P<0.05, in each). Conclusions: The diluted CM protocol facilitates more uniform attenuation on coronary CTA in comparison with the BW-adjusted protocol.  (Circ J 2014; 78: 662–670)

View full abstract

Background: The current screening strategy for subclinical coronary atherosclerosis in asymptomatic diabetic patients is not sufficient in real clinical practice. A new strategy was investigated that uses cardiac multi-detector computed tomography (MDCT) and a treadmill test (TMT). Methods and Results: A total of 445 self-referred asymptomatic diabetic patients underwent cardiac MDCT. The treatment plan was determined according to the new strategy that uses MDCT and TMT. All patients underwent clinical follow-up and cardiac events were investigated. The incidence of subclinical atherosclerosis was 49.4%. The group without plaque underwent clinical follow-up without treatment and did not experience any cardiac events in 675.1 person-years of follow-up. Among patients with subclinical atherosclerosis without significant stenosis (n=136) who received medical treatment only, 11 patients experienced cardiac events over 326.4 person-years. The patients with significant stenosis (n=84) underwent TMT. Patients with positive TMT (n=14) underwent coronary angiograms and revascularization therapy was performed in all of them over 39.2 person-years. Patients with negative TMT (n=70) underwent medical treatment, and 27 of them experienced cardiac events. The incidence of cardiac death was 0% during 3 years of follow-up. Conclusions: The new strategy for detecting subclinical atherosclerosis on MDCT combined with TMT may be a useful method for minimizing the mortality rate from cardiovascular disease in asymptomatic diabetic patients.  (Circ J 2014; 78: 671–678)

View full abstract

Background: Levels of platelet reactivity in patients on dual antiplatelet therapy (DAPT) can be influenced by concomitant treatment with statins. We verified if the pharmacodynamic effects of CYP3A4-metabolized statins (atorvastatin) and non-CYP3A4-metabolized statins (pitavastatin) differ in patients with coronary artery disease (CAD) treated with DAPT. Methods and Results: A total of 155 CAD patients receiving DAPT (clopidogrel 75mg plus aspirin 100mg) entered the PORTO trial. Patients were randomly assigned to atorvastatin (20mg day) or pitavastatin (4mg day) for 30 days, and then switched to the other drug for 30 days. Platelet reactivity was expressed as VerifyNow P2Y12 platelet response units (PRU) before and after each 30-day treatment period. High platelet reactivity was defined as PRU >208. As compared with pretreatment (192±49), PRU was significantly higher after 30-day atorvastatin (210±56; P=0.003), but was unchanged after 30-day pitavastatin (199±47 PRU, NS). In the 48 patients with PRU >208 at baseline (232±44), PRU increased significantly after 30-day atorvastatin (258±41, P=0.004), but not after 30-day pitavastatin (237±43, NS). In the 107 patients with PRU <208 at baseline (174±52), PRU did not change significantly with respect to baseline either after 30-day atorvastatin (188±61, NS) or after 30-day pitavastatin (181±59, NS). Conclusions: Pitavastatin, a non-CYP3A4-metabolized statin, does not affect clopidogrel’s response as compared with atorvastatin in patients who are borderline or poor responders to DAPT.  (Circ J 2014; 78: 679–684)

View full abstract

Background: Myocardial bridging (MB) results in compression of the coronary artery lumen in systole, extending into diastole with resultant hemodynamic alternation as reflected by fractional flow reserve (FFR). MB has also been associated with coronary endothelial dysfunction. The objective of this study was to investigate relationship between FFR with dobutamine challenge and coronary microvascular endothelial dysfunction in symptomatic MB. Methods and Results: Seventeen consecutive patients who had cardiac catheterization assessment of MB were enrolled. The patients were divided into 2 groups according to normal (% increase in coronary blood flow [%CBF] ≥50%, n=7) or impaired (%CBF <50%, n=10) coronary microvascular endothelial function assessed on vasoreactivity in the coronary artery with intracoronary infusion of acetylcholine (Ach). Myocardial ischemia was then assessed using FFR at rest and during i.v. dobutamine infusion challenge across the MB with intracoronary pressure wires. FFR was significantly decreased at peak dobutamine infusion compared to at rest in the impaired group (0.85±0.06 vs. 0.91±0.05, P=0.001), but not in the normal group (0.93±0.05 vs. 0.91±0.07, P=0.618). Both FFR at rest and at peak dobutamine infusion had a positive correlation with %CBF by Ach in the impaired group (r²=0.46, P=0.030; r²=0.52, P=0.018, respectively). Conclusions: Microvascular endothelial dysfunction was associated with decreased FFR at peak dobutamine stress in patients with symptomatic MB.  (Circ J 2014; 78: 685–692)

View full abstract

Background: Most patients with surgically corrected tetralogy of Fallot (TOF) are faced with multiple residua and sequelae such as pulmonary regurgitation (PR), resulting in reoperation for pulmonary valve replacement (PVR). Plasma brain natriuretic peptide (BNP) level and serum N-terminal pro-BNP (NT-pro-BNP) level are useful as diagnostic objective markers of chronic heart failure (CHF). The aim of the study was to examine whether these markers have predictive ability for reoperation in children with surgically corrected TOF. Methods and Results: Fifty-eight patients (38 male, 20 female) aged 1–18 years (median, 7 years) were enrolled. Serum NT-pro-BNP in TOF patients was significantly higher than in age-matched hospital controls without CHF (359.5±449.7pg/ml vs. 86.1±45.1pg/ml, respectively; P<0.0001). BNP and NT-pro-BNP had a better correlation with CHF index, RVEDP, and LVEDV in TOF groups. Children with surgically corrected TOF who had indication for PVR had higher BNP and NT-pro-BNP and more severe PR than those without indication for PVR. On multivariate logistic regression analysis, NT-pro-BNP was the strongest predictor for reoperation in patients with surgically corrected TOF. Area under the curve of NT-pro-BNP for reoperation was 0.950 (P<0.001) with a sensitivity of 88.9% and specificity of 91.8%. Conclusions: NT-pro-BNP is a good biomarker for monitoring CHF, and is a good predictor of PVR in children with surgically repaired TOF.  (Circ J 2014; 78: 693–700)

View full abstract

Background: Circumstances and outcomes of out-of-hospital cardiac arrest (OHCA) in elementary and middle school students while at school in the era of public-access defibrillation are unknown. Methods and Results: We conducted a nationwide hospital-based survey of elementary and middle school students who had had OHCA of cardiac origin and received prehospital resuscitation in 2005–2009. Among 58 cases recruited, 90% were witnessed by bystanders; 86% had ventricular fibrillation as the initial rhythm; 74% were resuscitated by bystanders; 24% were defibrillated by bystanders; 55% occurred at school; 66% were exercise-related; 48% were followed up before the event; 67% had structural heart disease. In total, 53% of overall patients and 79% of those initially defibrillated by bystanders had a favorable neurological outcome. Patients were more likely to be defibrillated by bystanders (38% vs. 8%, P=0.012) and had a more favorable neurological outcome in schools (69% vs. 35%, P=0.017) than in other locations. The majority of arrests in schools were exercise-related (84% vs. 42%, P=0.001), occurred at sports venues, and students were resuscitated by teachers; half of the cases at school occurred in patients with a pre-event follow-up. Conclusions: After OHCA, children were more likely to be defibrillated by bystanders and had a better outcome in schools than in other locations, which may be relevant to the circumstances of events.  (Circ J 2014; 78: 701–707)

View full abstract

Background: Epidemiology and clinical management of acute venous thromboembolism (VTE) are not readily available in Japan. Methods and Results: The Japan VTE Treatment Registry (JAVA) is a multicenter cohort study of consecutive patients with an objectively confirmed, symptomatic acute pulmonary embolism (PE), symptomatic acute deep vein thrombosis (DVT), or asymptomatic acute proximal DVT. Of the 1,076 patients enrolled with acute VTE, 68.7% presented with an isolated DVT; 17.0% had PE alone; and 14.4% had both. VTE management was characterized by a high rate of inferior vena cava filter insertion (40.6%), frequent thrombolysis (21.1%), and sub-therapeutic unfractionated heparin-based anticoagulation, followed by warfarin prescription, mostly targeting an international normalized ratio of 2.0 (range, 1.5–2.5). During a mean observation period of 252.5 days, 29 recurrent cases of VTE were documented, yielding an incidence rate of 3.9 per 100 patient-years. A total of 123 patients died during the study period, corresponding to a rate of 16.6 deaths per 100 patient-years. The incidence of major bleeding was 3.2% per patient-year, including 2 fatal hemorrhages and 7 intracranial hemorrhages. Conclusions: VTE management in Japan is characterized by a highly aggressive strategy in the acute phase, in contrast to protocols that use low-level anticoagulation. The VTE recurrence rates in Japan and Western countries are similar, but mortality is higher in Japan, with significant variability depending on patient and management characteristics.  (Circ J 2014; 78: 708–717)

View full abstract

Background: Postoperative cardiac events are an important cause of morbidity and mortality in patients undergoing non-cardiac surgery. Predictive values of surgical parameters with respect to development of postoperative cardiac events have not been well investigated. Methods and Results: This study included 1,016 consecutive patients who underwent cardiac consultation prior to elective non-cardiac surgery. A major adverse cardiac event (MACE) was defined as a composite of all-cause death, non-fatal myocardial infarction, and pulmonary edema within 30 days of surgery. There were 95 postoperative MACEs (9.4%). Patients with postoperative MACE were significantly older, and had significantly higher revised cardiac risk index than those without. ST-T change on electrocardiogram (ECG) was significantly higher in patients with postoperative MACE. Of the surgical parameters, significant differences in surgery time (317±211min vs. 189±112min, P<0.001), postoperative hemoglobin (10.7±1.9g/dl vs. 11.3±1.8g/dl, P=0.007), risk of surgery (P<0.001), and transfusion (37.6% vs. 6.6%, P<0.001) were observed between the 2 groups. On multivariate logistic regression analysis, surgery time (odds ratio [OR], 1.004; 95% confidence interval [CI]: 1.003–1.006, P<0.001) and need for transfusion (OR, 4.578; 95% CI: 2.599–8.065, P<0.001), as well as age and ST-T change on ECG were independent predictors of postoperative MACE. Conclusions: Surgical parameters, including surgery time and transfusion, can strongly predict development of postoperative MACE in patients undergoing non-cardiac surgery.  (Circ J 2014; 78: 718–723)

View full abstract

Background: Stem cells transplanted to the ischemic myocardium usually encounter massive cell death within a few days after transplantation, and hypoxic preconditioning (HPC) is currently used as a strategy to prepare stem cells for increased survival and engraftment in the heart. The purpose of this study is to determine whether Pim-1 kinase mediates any beneficial effects of HPC for human cardiac progenitor cells (CPCs). Methods and Results: Human CPCs were isolated from an adult heart auricle and were purified by magnetic-activated cell sorting using c-kit magnetic beads; they were hypoxic preconditioned for 6h. Both Pim-1 and p-Akt were determined. CPCs were assigned to one of the following groups: (1) control (without HPC); (2) HPC; or (3) HPC+I (Pim-1 inhibitor). HPC can promote the survival of CPCs. HPC enhances the expression of Pim-1 kinase in a time-dependent manner, which causes a reduction of proapoptotic elements (cytochrome c and cleaved caspase-3) and the preservation/modulation of important components of the mitochondria (Bcl-2, Bcl-XL and p-Bad), and attenuates mitochondrial damages. All of these protective effects were blocked by a Pim-1 inhibitor. Conclusions: Pim-1 plays a pivotal role in the protective effect of HPC for CPCs, and the promotion of the expression of Pim-1 in CPCs can as serve part of molecular therapeutic interventional strategies in the treatment of cardiomyopathy damage by blunting CPC death.  (Circ J 2014; 78: 724–731)

View full abstract

Background: Recent evidence indicates that vitamin D deficiency is associated with an increased risk of renal impairment, but studies addressing the influence of vitamin D deficiency on the development of chronic kidney disease (CKD) in the general Asian population have been few. Methods and Results: A total of 2,417 community-dwelling individuals without CKD stage 3–5 aged ≥40 years were followed for 5 years (mean age, 60 years; women, 59.1%). The cumulative incidence of CKD stage 3–5, defined as estimated glomerular filtration rate (eGFR) <60ml·min⁻¹·1.73m⁻², and the rate of decline in eGFR according to quartile of serum 1,25-dihydroxyvitamin D (1,25(OH)₂D), were estimated. During follow-up, 378 subjects experienced CKD stage 3–5. The age- and sex-adjusted incidence of CKD stage 3–5 increased significantly with decreasing serum 1,25(OH)₂D (P for trend <0.001). Compared with the highest quartile, the multivariate-adjusted odds ratio for the development of CKD stage 3–5 was 1.90 in the lowest quartile and 1.74 in the second lowest quartile, after adjusting for confounding factors. Additionally, lower serum 1,25(OH)₂D was significantly associated with a greater change in eGFR (−0.10ml·min⁻¹·1.73m⁻²·year⁻¹ per 10-pg/ml decrement in serum 1,25(OH)₂D). Conclusions: Lower serum 1,25(OH)₂D is a significant risk factor for the development of CKD stage 3–5 in the general Asian population.  (Circ J 2014; 78: 732–737)

View full abstract

Background: The features of acute aortogenic embolic stroke on magnetic resonance diffusion-weighted imaging (DWI) have not been fully elucidated, so we compared patients with acute aortogenic embolic stroke and those with acute cardioembolic stroke. Methods and Results: This study included 40 consecutive patients with acute aortogenic embolic stroke, and 40 age- and sex-matched patients with acute cardioembolic stroke. The diagnosis of aortogenic embolic stroke was made when patients met 5 criteria: (1)acute neurologic event lasting >24h; (2) positive signals on DWI; (3) atherosclerotic lesions ≥3.5-mm thick at the aortic arch on transesophageal echocardiography; (4) neuroradiologic features suggesting embolic stroke, such as lesions involving the brain cortex or the re-opening phenomenon of previously occluded vessels on Magnetic Resonance Angiography (MRA); and (5) absence of other embolic sources, including heart disease and carotid stenosis. The number, site, and maximal diameter of the infarct lesions on DWI were compared between the aortogenic and cardiogenic groups. The aortogenic patients more frequently had ≥3 lesions (25.0% vs. 2.5%, P<0.01), lesions with a maximal diameter <30mm (77.5% vs. 20.0%, P< 0.001), and vertebrobasilar system lesions (55.0% vs. 10.0%, P< 0.001) than the cardiogenic patients. Conclusions: Acute aortogenic embolic stroke is characterized by multiple (≥3) and small lesions, and involvement of the vertebrobasilar system.  (Circ J 2014; 78: 738–742)

View full abstract

Background: Notch signaling is a highly conserved pathway that promotes vascular and myocardial growth. The hypothesis that exogenous vascular endothelial growth factor (VEGF) administration to ischemic myocardium would enhance the neovascular response and upregulate Notch signaling was assessed. Methods and Results: Fourteen male Yorkshire swine underwent placement of an ameroid constrictor on the left circumflex artery to induce chronic myocardial ischemia with half of the animals receiving perivascular VEGF to the ischemic area. The remote territory served as the normal ventricle control (NV), while the 2 experimental groups consisted of the area at risk of the non-VEGF animals (AAR) and the area at risk of animals treated with VEGF (VEGF). Capillary and arteriolar density was significantly increased in the VEGF group as compared to both NV and AAR. Expression of Notch receptors and pro-neovascular Notch ligands was significantly higher in the VEGF group. Both Jagged 1 and Notch 3 were the most highly concentrated in the smooth muscle wall of arterioles. Conclusions: VEGF administration to chronically ischemic myocardium significantly augmented the neovascular response by an increase in both capillary and arteriolar density, and resulted in an upregulation of several Notch receptors and ligands, which were not upregulated with ischemia alone. These findings suggest that the augmented neovascular response seen with VEGF administration was through the VEGF-induced upregulation of Notch signaling.  (Circ J 2014; 78: 743–751)

View full abstract

Background: Vascular endothelial growth factor (VEGF) is associated with Kawasaki disease (KD), the most commonly acquired heart disease in developed countries. This study investigated the involvement of VEGF-A expression and its related signaling pathway in Lactobacillus casei cell wall extract (LCWE)-induced murine coronary artery lesions (CALs), and analyzed this in regard to the inhibition of CALs by spleen tyrosine kinase (Syk). Methods and Results: Wild-type BALB/C mice were intraperitoneally injected with LCWE (1mg/ml) to induce CALs. The aortic roots, ventricular myocardium, peripheral blood leukocytes (PBLs), spleen, liver, kidneys, and lungs were analyzed for VEGF-A expression. Phosphate buffered saline (PBS)-, lipopolysaccharide (LPS)-, and zymosan-treated mice served as controls, and an oral Syk inhibitor served as an arteritis-ameliorated reagent. In aortic roots and PBLs, LCWE induced an early upregulation and a late downregulation of VEGF-A expression. No differential VEGF-A expression was observed in the other organs. Most importantly, Syk inhibition significantly attenuated the LCWE-induced expression of VEGF-A, dimethylarginine dimethylaminohydrolase (DDAH)-1, and endothelial nitric oxide synthase in aortic roots. However, LCWE-induced aortic DDAH-2 expression remained higher, despite Syk inhibition. Conclusions: Local VEGF-A and its signaling pathway are associated with the development of LCWE-induced CALs. Therefore, the clinical correlation between VEGF and human KD and the role of the VEGF-A regulation and signaling pathway in murine CALs warrant further investigation.  (Circ J 2014; 78: 752–762)

View full abstract

Background: Prothrombin time (PT) distribution in Japanese nonvalvular atrial fibrillation (NVAF) patients under rivaroxaban therapy remains to be clarified. Methods and Results: Between May 2012 and July 2013, 115 NVAF patients received rivaroxaban (PT was measured in 94; reagent: recombiplastin). In these patients, (1) PT values were distributed widely from patient to patient and from peak to trough, (2) the time-dependence was obscure with sampling at any time in the outpatient clinic, and (3) the incidence of adverse events was too low for analyzing the relation with PT. Conclusions: We report the distribution of PT for Japanese NVAF patients under rivaroxaban therapy in real-world clinical practice.  (Circ J 2014; 78: 763–766)

View full abstract

(Circ J 2007; 71: 1199–1207)

View full abstract

(Circ J 2014; 78: 267–270)

View full abstract